KR101831553B1 - Novel compounds for treatment of metastatic blast cancer and medical use thereof - Google Patents

Abstract

The present invention relates to a useful novel compound of metastatic breast cancer and medical use thereof. According to the present invention, an N-(6-methoxy-3-nitropyridin-2-yl)-1H-indol-5-amine, an N-(6-methoxy-3-nitropyridin-2-yl)-1H-indol-6-amine, an N-(6-methoxy-3-nitropyridin-2-yl)-1H-benzo[d]imidazol-5-amine and an N-(6-methoxy-3-nitropyridin-2-yl)-1H-benzo[d]triazol-5-amine suppress a cell survival rate of a metastatic breast cancer cell to prevent breast cancer or to be used as a pharmaceutical composition or a health food composition for preventing or improving breast cancer wherein the N-(6-methoxy-3-nitropyridin-2-yl)-1H-indol-5-amine, the N-(6-methoxy-3-nitropyridin-2-yl)-1H-indol-6-amine, the N-(6-methoxy-3-nitropyridin-2-yl)-1H-benzo[d]imidazol-5-amine and the N-(6-methoxy-3-nitropyridin-2-yl)-1H-benzo[d]triazol-5-amine are novel synthesized compounds.

Description

≪ Desc / Clms Page number 2 > Novel compounds for metastatic breast cancer and medical use thereof

The present invention relates to novel compounds of metastatic breast cancer and their medical uses.

According to the National Statistical Office, deaths from cancer are the number one cause of death among Koreans. Cancer is a disease in which cells are abnormally developed in the cell cycle that constitutes the human tissue and the cells do not normally differentiate and continue to divide. There are three stages of initiation (initiation), promotion, and progression . The cause of cancer is mutation in normal cell gene or cancer suppressor gene by the carcinogenic substance contained in environment or food, and it is known that such cells form cancer tissue by abnormal proliferation while being continuously stimulated by carcinogen, The cause of cancer has not yet been clearly elucidated.

Among them, breast cancer is the most common malignant disease in women. In Korea, the fifth most common cause of cancer was stomach cancer, lung cancer, liver cancer, and colorectal cancer, accounting for 6.5% (5,444) of total cancer incidence in 2005. According to the report of the Ministry of Health and Welfare Central Cancer Registry, And 16.8% of the tumors. In breast cancer, early detection is more important than other cancers, as cancer cells invade surrounding tissues or begin to metastasize to the lymph nodes.

Cancer is divided into benign tumor and malignant tumor. Benign tumors have relatively slow growth rate and do not develop metastasis which is transferred from the origin of tumor to other tissues. However, malignant tumors Is a very important cause of life-threatening and death by having the characteristic of rapid growth that invades other tissues from the origin.

Although surgery, radiation therapy, and chemotherapy are used for the treatment of cancer, more than 50% of all cancer patients are reported to die without treatment. The reason for this is that even if surgical resection is performed, cancer can not be removed due to the failure to remove the cancer cells that have been metastasized, or cancer treatment using an anticancer agent despite the development of various cancer drugs, Although the tumor seems to be diminishing in response, cancer cells that develop resistance to anticancer drugs after treatment or treatment are rapidly multiplying. Today, about 60 kinds of various anticancer drugs are used, and knowledge about the characteristics of cancer development and cancer cells is well known, so that researches on the development of new anticancer drugs are actively under way. However, when cancer drugs are repeatedly administered for a long period of time or when cancer is recurred, there is a disadvantage that the cancer cells lose the therapeutic effect by acquiring resistance to the cancer drug. In addition, most anticancer drugs have the effect of inhibiting the synthesis of nucleic acid in the cell or directly binding to nucleic acid to impair its function. These anticancer drugs do not only act selectively on cancer cells, but also on normal cells, Which causes various side effects such as a decrease in bone marrow function, gastrointestinal mucosal damage, hair loss, and the like. In addition, radiation therapy is also difficult to cure due to the appearance of cancer cells having resistance to radiation. Therefore, it is necessary to develop a new therapeutic agent for cancer treatment.

Korean Registered Patent No. 10-1341195 (Registered on Dec. 06, 2013)

It is an object of the present invention to provide useful novel compounds of metastatic breast cancer and their pharmaceutically acceptable salts.

It is still another object of the present invention to provide a pharmaceutical composition for preventing or treating breast cancer, or a health food composition for preventing or improving breast cancer, containing the novel compound and a pharmaceutically acceptable salt thereof as an active ingredient.

In order to achieve the above object, the present invention provides a compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

Wherein R ₁ is methoxy and R ₂ is selected from the group consisting of indole, benzimidazole and benzotriazole.

The present invention also provides a pharmaceutical composition for preventing or treating breast cancer or a composition for preventing or improving breast cancer, which comprises a compound represented by the following formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[Chemical Formula 1]

Wherein R ₁ is methoxy and R ₂ is selected from the group consisting of indole, benzimidazole and benzotriazole.

(6-methoxy-3-nitropyridin-2-yl) -1H-indol-5-amine synthesized in the present invention, N- Benzo [d] imidazol-5-amine and N- (6-methoxy-3 -Nitropyridin-2-yl) -1H-benzo [d] [1,2,3] triazol-5-amine is useful as a pharmaceutical composition for preventing or treating breast cancer by inhibiting the cell survival rate of metastatic breast cancer cells, It can be utilized as a health food composition for improvement.

The inventors of the present invention synthesized a compound having various indazole derivatives and indazole derivatives in 2-chloro-6-methoxy-3-nitropyridine to synthesize a novel compound of 5b to 5e, Inhibited cell proliferation of MDA-MB-231 cells.

The present invention provides a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

Wherein R ₁ is methoxy and R ₂ is selected from the group consisting of indole, benzimidazole and benzotriazole.

The present invention also provides a pharmaceutical composition for preventing or treating breast cancer, which comprises a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

[Chemical Formula 1]

Wherein R ₁ is methoxy and R ₂ is selected from the group consisting of indole, benzimidazole and benzotriazole.

Preferably, the compound or a pharmaceutically acceptable salt thereof is N- (6-Methoxy-3-nitropyridin-2-yl) -1H- indol- (6-Methoxy-3-nitropyridin-2-yl) -1H-indol-5-amine, N- -nitropyridin-2-yl) -1H-indol-6-amine, N- (6-methoxy-3-nitropyridin- Benzo [d] imidazol-5-amine and N- (6-methoxy-3-nitropyridin-2-yl) ] [1,2,3] triazol-5-amine (N- (6-Methoxy-3-nitropyridin- , But it is not limited thereto.

Preferably, the compound or a pharmaceutically acceptable salt thereof may inhibit cell proliferation of breast cancer cells.

Preferably, the breast cancer may be, but is not limited to, metastatic breast cancer.

Preferably, the pharmaceutically acceptable salt is selected from the group consisting of a sodium salt, a potassium salt, a calcium salt, a lithium salt, a magnesium salt, a cesium salt, an aminium salt, an ammonium salt, a triethylammonium salt and a pyridinium salt But not limited to, one or more basic salts selected from the group consisting < RTI ID = 0.0 > of: < / RTI >

Preferably, the pharmaceutically acceptable salt is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, May be one or more acidic salts selected from the group consisting of malonic acid, glutaric acid, acetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid and arpartic acid , But not limited to,

When the composition of the present invention is a pharmaceutical composition, it may contain a pharmaceutically acceptable carrier in addition to the above-mentioned active ingredients. Such pharmaceutically acceptable carriers are those conventionally used in pharmaceutical preparations, and include lactose, dextrose, The present invention relates to a process for the preparation of a medicament for the treatment and / or prophylaxis of cancer, comprising administering a therapeutically effective amount of a compound selected from the group consisting of cross, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, Carboxymethylcellulose, carboxymethylcellulose, hydroxybenzoate, talc, magnesium stearate, mineral oil, and the like. The pharmaceutical composition may further contain a filler, a weight agent, a binder, a lubricant, a wetting agent, a disintegrant, a sweetener, a flavoring agent, an emulsifying agent, a suspending agent, a fragrance, a preservative and the like as an additive and an auxiliary agent.

The pharmaceutical composition may be formulated into tablets, pills, powders, granules, capsules, suspensions, solutions, emulsions, syrups, sterilized aqueous solutions, nonaqueous solutions, emulsions, lyophilized preparations, suppositories and sterile injectable solutions.

The pharmaceutical composition may be administered by intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, subcutaneous, intradermal, intranasal, intrapulmonary, intraocular, intramuscular, Rectally, topically, orally, and by inhalation.

An effective amount of the active ingredient of the above pharmaceutical composition means an amount required for prevention or treatment of the disease. Accordingly, the present invention is not limited to the particular type of the disease, the severity of the disease, the kind and amount of the active ingredient and other ingredients contained in the composition, the type of formulation and the patient's age, body weight, general health status, sex and diet, But are not limited to, various factors, including, for example, the rate of administration, the rate of administration, the duration of the treatment, the drugs used concurrently.

The present invention also provides a health food composition for preventing or ameliorating breast cancer, which comprises a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

[Chemical Formula 1]

Wherein R ₁ is methoxy and R ₂ is selected from the group consisting of indole, benzimidazole and benzotriazole.

Preferably, the compound or a pharmaceutically acceptable salt thereof is N- (6-Methoxy-3-nitropyridin-2-yl) -1H- indol- (6-Methoxy-3-nitropyridin-2-yl) -1H-indol-5-amine, N- -nitropyridin-2-yl) -1H-indol-6-amine, N- (6-methoxy-3-nitropyridin- Benzo [d] imidazol-5-amine and N- (6-methoxy-3-nitropyridin-2-yl) ] [1,2,3] triazol-5-amine (N- (6-Methoxy-3-nitropyridin- , But it is not limited to this.

Preferably, the breast cancer may be, but is not limited to, metastatic breast cancer.

The health food composition may be provided in the form of powder, granules, tablets, capsules, syrups or beverages. The health food composition may be used in combination with other food or food additives other than the active ingredient, . The amount of the active ingredient to be mixed can be suitably determined according to its use purpose, for example, prevention, health or therapeutic treatment.

The effective dose of the active ingredient contained in the health food composition may be used in accordance with the effective dose of the pharmaceutical composition. However, in the case of long-term consumption intended for health and hygiene purposes or health control purposes, And it is clear that the active ingredient can be used in an amount exceeding the above range since there is no problem in terms of safety.

There is no particular limitation on the type of the health food, and examples thereof include meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, Drinks, alcoholic beverages and vitamin complexes.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

Example  1: Reagent And devices

The reagents used in this experiment were Sigma-Aldrich (Sigma, St. Louis, MO, USA), acros organics (Thermo Fisher Scientific In., Gell, Belgium) and alfa aesar , Johnson Mattey Company, Karlsruhe, Germany). Most reagents were used without further purification. Synthesis experiments were conducted under argon or in the atmosphere, and recrystallization was used to purify the product after synthesis.

Silica gel plates (silica gel 6 F254, 25 mm) were purchased from Merck (Darmstadt, Germany) for thin layer chromatography (TLC) experiments.

The structure of the compound was analyzed by measuring ¹ H and ¹³ C nuclear magnetic resonance (NMR) spectra using JNM-ECZR 500 (JEOL, Tokyo, Japan). NMR solvent (CD _{3) 2} SO was used a (euriso-top), the chemical shift values (δ) are exhibited by ppm peak is s (single), d (doublet ), t (triplet), m (multiplet) And dd (doublet of doublet).

For the biological activity evaluation, an image analyzer (Fuji, Tokyo, Japan) and a microplate reader (TECAN, Mannedorf, Switerland) were used.

Example  2: Compound Synthesis

1) N- (6- Methoxy -3- Nitropyridine 2-yl) -1H-indol-5-amine (Compound 5b)

2-Chloro-6-methoxy-3-nitropyridine (0.10 g, 0.53 mmol), 5-aminobenzimidazole (0.07 g, 0.53 mmol) and trimethylamine (TMA) (0.08 mL, 0.58 mmol) were dissolved in methanol, and the mixture was stirred at 120 ° C for 18 hours. After cooling in the atmosphere, water was slowly added and stirred for 30 minutes. The resulting solid product was filtered off, washed with methanol and dried to give compound 5b (61% yield).

¹ H NMR (500 MHz, DMSO- d ₆ )? 11.13 (s, 1H), 10.53 (s, 1H), 8.14 (d, J = 9 Hz, 1H), 7.87 (s, 1H), 7.41-7.31 m, 3H), 6.43 (s, 1H), 6.30 (d, J = 9 Hz, 1H), 3.83 (s, 3H). ^{13 C NMR (125 MHz, DMSO} -d 6) δ 166.2, 150.7, 138.4, 133.5, 129.2, 127.6, 126.2, 121.6, 118.0, 114.5, 111.2, 101.8, 101.3, 54.5.

2) N- (6- Methoxy -3- Nitropyridine Yl) -1H-indole-6- Amine (N- (6- Methoxy -3-nitropyridin-2-yl) -1H-indol-6-amine) (Compound 5c)

5-aminoindole (0.07 g, 0.53 mmol) and trimethylamine (0.08 mL, 0.58 mmol) were added to a solution of 2-chloro-6-methoxy-3-nitropyridine (0.10 g, 0.53 mmol) After dissolving, the mixture was stirred at 120 DEG C for 18 hours. After cooling in the atmosphere, water was slowly added and stirred for 30 minutes. The resulting solid product was filtered off, washed with methanol and dried to give compound 5c (76% yield).

^{1 H NMR (500 MHz, DMSO} -d 6) δ 11.13 (s, 1H), 10.53 (s, 1H), 8.41 (d, J = 9.0 Hz, 1H), 7.87 (s, 1H), 7.41-7.31 ( m, 3H), 6.43 (s, IH), 6.30 (d, J = 9.0 Hz, IH), 3.83 (s, 3H). ¹³ C NMR (125 MHz, DMSO-d ₆ )? 166.2, 150.6, 138.4, 133.5, 129.2, 127.5, 126.1, 121.6, 118.0, 114.4, 111.1, 101.7, 101.3, 54.5.

3) N- (6- Methoxy -3- Nitropyridine Yl) -1H- Benzo [d] indazole -5- Amine Benzo [d] imidazol-5-amine) (Compound 5d)

6-aminoindole (0.07 g, 0.53 mmol) and trimethylamine (TEA) (0.08 mL, 0.53 mmol) were added to a solution of 2-chloro-6-methoxy- 0.58 mmol) were dissolved in methanol, and the mixture was stirred at 120 ° C for 18 hours. After cooling in the atmosphere, water was slowly added and stirred for 30 minutes. The resulting solid product was filtered off, washed with methanol and dried to give compound 5d (90% yield).

^{1 H NMR (500 MHz, DMSO} -d 6) δ 11.20 (s, 1H), 10.60 (s, 1H), 8.40 (d, J = 9.0 Hz, 1H), 8.0 (s, 1H), 7.50 (d, J = 8.5 Hz, 1 H), 3.90 (s, 3 H). ^{13 C NMR (125 MHz, DMSO} -d 6) δ 166.2, 150.1, 138.5, 135.8, 131.4, 125.6, 124.8, 121.8, 119.7, 115.2, 105.3, 101.9, 101.0, 54.8.

4) N- (6- Methoxy -3- Nitropyridine Yl) -1H- Benzo [d] [1,2,3] triazole -5- Amine D] [1,2,3] triazol-5-amine) (Compound 5e)

5-amino-1H-benzotriazole (0.09 g, 0.69 mmol) and triethylamine (0.13 g, 0.69 mmol) were added to a solution of 2-chloro-6-methoxy- (0.11 mL, 0.76 mmol) were dissolved in methanol, and the mixture was stirred at 120 DEG C for 24 hours. After cooling in the atmosphere, water was slowly added and stirred for 30 minutes. The resulting solid product was filtered off, washed with methanol and dried to give compound 5e (61% yield).

^{1 H NMR (500 MHz, DMSO} -d 6) δ 10.62 (s, 1H), 8.47 (d, J = 9.5 Hz, 1H), 8.37 (s, 1H), 7.92 (d, J = 9.5 Hz, 1H) , 7.62 (d, J = 8.5 Hz, 1H), 6.42 (d, J = 9.5 Hz, 1H), 3.90 (s, 3H).

Reaction formulas and yields of the compounds synthesized in Example 2 are shown in the following Reaction Scheme 1 and Table 1.

[Reaction Scheme 1]

R ₂ Yield (%) product One

61 5b 2

76 5c 3

90 5d 4

61 5e

Example  3: Cell culture

MDA-MB-231 cells, a breast cancer cell line, were purchased from ATCC (American Type Culture Collection, Rockville, Md., USA) and were cultured in DMEM supplemented with 10% fetal bovine serum (FBS) The cells were subcultured 2-3 times in a DMEM medium supplemented with penicillin / streptomycin at 37 ° C in a 5% CO ₂ incubator on a weekly basis.

Example  4: Measurement of cell viability

MTT (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide) analysis was performed to confirm cell viability by the compound synthesized using MDA-MB-231 cells. When approximately 80% of the cells were grown on the plate, the cells were diluted with DMEM medium to a concentration of 2 × 10 ³ cells / well. Then, 100 μL of the cell suspension was added to each well of the 96-well plate and cultured for 14 hours. The compounds were cultured for 3 days after being changed into cultures treated with each concentration (5b to 5e: 0, 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 30, 50, 70, 100 μM). Then, 10 μL of MTT reagent was added to each well, followed by reaction at 37 ° C. in a 5% CO ₂ incubator for 4 hours. Then, the culture solution was removed, and 100 μL of dimethyl sulfoxide (DMSO) was added to each well. The absorbance of formazan, a reaction product, was measured at 560/690 nm using a microplate reader, and the cell viability by concentration was expressed as EC ₅₀ (μM).

As a result, the EC ₅₀ values of the compounds 5b to 5e were 28.18, 69.18, 44.67 and 34.46 μM, respectively, and the cell survival rate of metastatic breast cancer cells was effectively suppressed in the order of 5b, 5e, Respectively.

compound R ₁ R ₂ MDA-MB-231
(EC ₅₀ ; μM) 5b

28.18 5c

69.18 5d

44.67 5e

34.46

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is clearly understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the invention. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

The scope of the present invention is defined by the appended claims, and all changes or modifications derived from the meaning and scope of the claims and their equivalents should be construed as being included within the scope of the present invention.

Claims (10)

1. A compound represented by the following formula (1): < EMI ID =
[Chemical Formula 1]

Wherein R ₁ is methoxy and R ₂ is selected from the group consisting of indole, benzimidazole and benzotriazole. A pharmaceutical composition for preventing or treating breast cancer, comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
[Chemical Formula 1]

Wherein R ₁ is methoxy and R ₂ is selected from the group consisting of indole, benzimidazole and benzotriazole. 3. The compound of claim 2 wherein said compound or pharmaceutically acceptable salt thereof is N- (6-methoxy-3-nitropyridin-2-yl) -1H- indol- 3-nitropyridin-2-yl) -1H-indol-5-amine, N- (6-Methoxy- 3-nitropyridin-2-yl) -1 H-benzo [d] imidazol-5-amine ( Benzo [d] imidazol-5-amine and N- (6-methoxy-3-nitropyridin-2-yl) [d] [1,2,3] triazol-5-amine (N- (6-Methoxy-3-nitropyridin- amine). < / RTI > The pharmaceutical composition for preventing or treating breast cancer according to claim 2, wherein the compound or a pharmaceutically acceptable salt thereof inhibits cell proliferation of breast cancer cells. 3. The pharmaceutical composition for preventing or treating breast cancer according to claim 2, wherein the breast cancer is metastatic breast cancer. The pharmaceutical composition according to claim 2, wherein the pharmaceutically acceptable salt is selected from the group consisting of a sodium salt, a potassium salt, a calcium salt, a lithium salt, a magnesium salt, a cesium salt, an aminium salt, an ammonium salt, a triethylammonium salt and a pyridinium salt ≪ RTI ID = 0.0 > 1, < / RTI > or a pharmaceutically acceptable salt thereof. The composition of claim 2, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, sulfurous acid, phosphoric acid, citric acid, acetic acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic acid, benzenesulfonic acid, At least one acidic salt selected from the group consisting of oxalic acid, malonic acid, glutaric acid, acetic acid, gluconic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid and arpartic acid Or a pharmaceutically acceptable salt thereof. A health food composition for preventing or ameliorating breast cancer, comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
[Chemical Formula 1]

Wherein R ₁ is methoxy and R ₂ is selected from the group consisting of indole, benzimidazole and benzotriazole. 9. The compound of claim 8, wherein said compound or pharmaceutically acceptable salt thereof is N- (6-methoxy-3-nitropyridin-2-yl) 3-nitropyridin-2-yl) -1H-indol-5-amine, N- (6-Methoxy- 3-nitropyridin-2-yl) -1 H-benzo [d] imidazol-5-amine ( Benzo [d] imidazol-5-amine and N- (6-methoxy-3-nitropyridin-2-yl) [d] [1,2,3] triazol-5-amine (N- (6-Methoxy-3-nitropyridin- aminolevulinic acid or a pharmaceutically acceptable salt thereof. The health food composition according to claim 8, wherein the breast cancer is metastatic breast cancer.